"Photodynamic Therapy" (PDT) is based upon the selective retention of porphyrin agents by neoplastic tissues. When injected intravenously, porphyrins localize at higher levels in malignant tumor tissues than in normal tissues. These same porphyrins also emit a characteristic dual-peaked red fluorescence after being exposed to light containing the appropriate wavelength to excite fluorescence. Porphyrins can be activated by light to catalyze the production of singlet oxygen from available triplet oxygen. Although the exact mechanism of necrosis is unclear, it has been suggested that the reactive singlet oxygen oxidizes unsaturated carbon-carbon bonds in amino acids and fatty acids. The ensuing loss of the structural integrity of cellular macromolecules results in cytocidal effects and tumor necrosis.
The initial experience with PDT centered on hematoporphyrin derivative (HPD) because of its attractive properties of tumor localization, low toxicity, photodynamic activity and absorption in the red spectrum (.about.630 nm). Notwithstanding these advantages, however, HPD has one main disadvantage, that being its tendency to accumulate in the skin and cause a prolonged skin photosensitivity. In recent years, however, a more purified version of HPD, known commercially as Photofrin, Porfimer Sodium (hereinafter "Photofrin") has been used in clinical trials. Photofrin contains dihematoporphyrin ether (DHE), the agent primarily responsible for the tumor localizing and photosensitizing activity of the drug. After irradiation by blue light, Photofrin emits an intense dual peaked red fluorescence that can be detected and analyzed.
Benzoporphyrin derivative monoacid-A (BDP-MA), another photosensitizing agent, is a benzo-derivative of photoporphyrin IX. In addition to its powerful phototoxicity, BPD-MA has a characteristic absorption maximum around 700 nm, which permits use of light with greater penetration depths. BPD-MA also appears to have lower skin concentrations and a shorter accumulation time at therapeutic levels than HPD, resulting in dramatically decreased photosensitivity of the skin of animals undergoing photodynamic therapy. After excitation by blue light, BPD-MA emits a characteristic red fluorescence peak at approximately 690 nm.
Many other compounds, such as modified porphyrins, chlorins, phthalocynines and purpurins may be useful as photosensitizers. In addition, silicon naphthalocynines, texaphyrins and other extended macrocycles containing tetrapurroles such as porphycenes and plotyrins may also be used as photosensitizers.
PDT optimization, however, requires a knowledge of the time course of drug concentration and selectivity of drug for tumors. In spite of significant recent progress, many of the detailed chemical and biochemical aspects of porphyrin sensitized PDT remain to be elucidated. These include the mechanism of its absorption, distribution and clearance from the body as well as the precise nature of the localizing and photosensitizing components.
Much of the research involving the determination of porphyrin tissue levels has involved radiolabelled porphyrin preparations (.sup.14 C or .sup.3 H) and/or the chemical extraction of the porphyrin agent from tissue biopsies. These techniques have a number of limitations, including exposing the patient to the hazards of radioactivity, the need to sacrifice a large number of animals and the poor spatial and temporal resolution practically obtainable. Additional problems and limitations are encountered in radiolabelling the photosensitizer. For instance, tritrium labelled HPD prepared by catalytic exchange may exchange again in vivo thereby obscuring results. On the other hand, tritium catalytic exchange of whole HPD, as opposed to one of its simple precursors (i.e., HP), could result in the labelling of any one or more of the numerous components in HPD. Although .sup.14 C photosensitizers theoretically should not undergo an in vivo exchange, unequal data has been obtained in pharmacological studies. Laser induced fluorescence measurements of drug biodistribution overcomes many of these disadvantages.